Title

Author

Date of Award

Degree Name

Doctor of Philosophy

College

Joan C. Edwards School of Medicine

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Vincent E Sollars

Second Advisor

Todd Green

Third Advisor

Richard M Niles

Abstract

Acute myelogenous leukemia (AML) is the deadliest of the lymphatic and bone marrow cancers. Patients diagnosed with AML have a five year survival rate of 23.4%. AML is characterized by an accumulation of undifferentiated and functionless myeloid precursors in the bone marrow and blood. Heat shock protein 90 (Hsp90) inhibitors, such as 17-AAG, an analog of geldanamycin (GM), are currently undergoing phase I, and II and III clinical trials for various cancers with mixed results. I found distinct responses to 17-AAG treatment among the AML cell lines tested. I also discovered two mutant TP53 alleles in Kasumi-3 cells, an AML cell line that was very sensitive to 17-AAG. I hypothesized that this high sensitivity was due to the degradation of mutant p53, a known Hsp90 binding protein. Although I was not able to show that this mutant p53 was acting in an oncogenic fashion, it still raises the possibility that tailoring 17-AAG treatment to patients with known oncogenic TP53 alleles might prove to be very effective. Kasumi-3 cells will provide a valuable model to determine which biomarkers may indicate sensitivity to Hsp90 inhibition. In addition to studying the role of Hsp90 inhibition in cancer, I also explored the hypothesis that Hsp90 acts as a morphological capacitor for evolution in a mammalian model. EML cells were used as a model for hematopoiesis and treated with GM to inhibit Hsp90. It was postulated that this treatment would cause a trans-differentiation event or have an effect on differentiation. What was observed was an increase in GM treated cell survival when selective conditions were applied. This data suggests that GM treatment was giving the cells a selective advantage. Unfortunately, experimental results were very variable and I was unable to obtain consistent results upon numerous replicate experiments. The various diverse responses to Hsp90 inhibition presented in these studies may help explain the mixed results of 17-AAG in clinical trials.